Stapled BIG3 helical peptide ERAP potentiates anti-tumour activity for breast cancer therapeutics.

Scientific Reports
Tetsuro YoshimaruToyomasa Katagiri

Abstract

Estradiol (E2) and the oestrogen receptor-alpha (ERα) signalling pathway play pivotal roles in the proliferative activity of breast cancer cells. Recent findings show that the brefeldin A-inhibited guanine nucleotide-exchange protein 3-prohibitin 2 (BIG3-PHB2) complex plays a crucial role in E2/ERα signalling modulation in breast cancer cells. Moreover, specific inhibition of the BIG3-PHB2 interaction using the ERα activity-regulator synthetic peptide (ERAP: 165-177 amino acids), derived from α-helical BIG3 sequence, resulted in a significant anti-tumour effect. However, the duration of this effect was very short for viable clinical application. We developed the chemically modified ERAP using stapling methods (stapledERAP) to improve the duration of its antitumour effects. The stapledERAP specifically inhibited the BIG3-PHB2 interaction and exhibited long-lasting suppressive activity. Its intracellular localization without the membrane-permeable polyarginine sequence was possible via the formation of a stable α-helix structure by stapling. Tumour bearing-mice treated daily or weekly with stapledERAP effectively prevented the BIG3-PHB2 interaction, leading to complete regression of E2-dependent tumours in vivo. Most importantly,...Continue Reading

References

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Datasets Mentioned

BETA
GSE87378

Methods Mentioned

BETA
xenograft
xenografts
surface plasmon resonance
co-immunoprecipitation
amidation
nuclear translocation
RNAseq
acetylation
flow cytometry

Software Mentioned

DAVID ( The Database for Annotation , Visualization and Integr...
BIAevaluation
GeneMANIA
CellQuest

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